title: Hyaluronic acid-based hydrogels containing covalently integrated drug depots: implication for controlling inflammation in mechanically stressed tissues.
abstract: Synthetic hydrogels containing covalently integrated soft and deformable drug depots capable of releasing therapeutic molecules in response to mechanical forces are attractive candidates for the treatment of degenerated tissues that are normally load bearing. Herein, radically cross-linkable block copolymer micelles (xBCM) assembled from an amphiphilic block copolymer consisting of hydrophilic poly(acrylic acid) (PAA) partially modified with 2-hydroxyethyl acrylate, and hydrophobic poly(n-butyl acryclate) (PnBA) were employed as the drug depots and the microscopic cross-linkers for the preparation of hyaluronic acid (HA)-based, hydrogels. HA hydrogels containing covalently integrated micelles (HAxBCM) were prepared by radical polymerization of glycidyl methacrylate (GMA)-modified HA (HAGMA) in the presence of xBCMs. When micelles prepared from the parent PAA-b-PnBA without any polymerizable double bonds were used, hydrogels containing physically entrapped micelles (HApBCM) were obtained. The addition of xBCMs to a HAGMA precursor solution accelerated the gelation kinetics and altered the hydrogel mechanical properties. The resultant HAxBCM gels exhibit an elastic modulus of 847 ± 43 Pa and a compressive modulus of 9.2 ± 0.7 kPa. Diffusion analysis of Nile Red (NR)-labeled xBCMs employing fluorescence correlation spectroscopy confirmed the covalent immobilization of xBCMs in HA networks. Covalent integration of dexamethasone (DEX)-loaded xBCMs in HA gels significantly reduced the initial burst release and provided sustained release over a prolonged period. Importantly, DEX release from HAxBCM gels was accelerated by intermittently applied external compression in a strain-dependent manner. Culturing macrophages in the presence of DEX-releasing HAxBCM gels significantly reduced cellular production of inflammatory cytokines. Incorporating mechano-responsive modules in synthetic matrices offers a novel strategy to harvest mechanical stress present in the healing wounds to initiate tissue repair.
authors.affiliation: Department of Materials Science and Engineering, ‡Delaware Biotechnology Institute, and §Biomedical Engineering Program, University of Delaware , Newark, Delaware 19716, United States.
authors.forename: Longxi
authors.initials: L
authors.lastname: Xiao
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Tong
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Chen
authors.forename: Darrin J
authors.initials: DJ
authors.lastname: Pochan
authors.forename: Chandran R
authors.initials: CR
authors.lastname: Sabanayagam
authors.forename: Xinqiao
authors.initials: X
authors.lastname: Jia
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003907:Dexamethasone / Q000737:chemistry* / Q000494:pharmacology; D006820:Hyaluronic Acid / Q000737:chemistry*; D020100:Hydrogels / Q000138:chemical synthesis / Q000737:chemistry*; D007249:Inflammation / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008823:Micelles; D008958:Models, Molecular; D015394:Molecular Structure; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D013499:Surface Properties
chemical_list: D016207:Cytokines; D020100:Hydrogels; D008823:Micelles; D011108:Polymers; D003907:Dexamethasone; D006820:Hyaluronic Acid